Systemic

Response to
Injury and
Metabolic
Support
 Introduction and Definitions
 Trauma is the leading cause of mortality and morbidity in patients under 45
y/o
 Peaks in the 2nd decade of life
 Older trauma victims have become more frequent
 Higher mortality even after taking into account comorbidity and extent of injury.
 Trauma accounts for 10% of deaths and 16% of disabilities worldwide (more
than malaria, TB, and HIV/AIDS combined)
 Injury causes the release of
damage-associated molecules
locally or systemically
 Leads to the inflammatory response
 Minor host insult: localized,
transient inflammatory response;
usually beneficial
 Major host insult:
 Die within 24 hrs: Overwhelming
tissue injury and multi-organ failure
 Die within a few weeks: Secondary
organ damage remote from injury site
 Persistent inflammation,
immunosuppression, and
catabolism syndrome (PICS):
extended ICU stay, complications post
discharge, failure to return to pre-
injury status
 Traumatic injury activates
innate immune system
 Produces a systemic Clinical spectrum of infection and systemic inflammatory response
inflammatory response syndrome
(SIR) Infection Identifiable source of microbial insult
SIRS Two or more of following criteria are met:
 To limit damage and Temperature ≥38°C (100.4°F) or ≤36°C (96.8°F)
restore homeostasis Heart rate ≥90 beats per minute
Respiratory rate ≥20 breaths per minute or Paco2 ≤ 32
 Simultaneous responses mmHg or mechanical ventilation
occur following severe Abnormal white blood cell count (≥12,000/μL or
traumatic injury: ≤4000/μL or ≥10% immature band forms)
 Proinflammatory: Sepsis Identifiable source of infection + SIRS
recognition of ligands Severe sepsis Sepsis + organ dysfunction
 Anti-inflammatory: Septic shock Sepsis + cardiovascular collapse (requiring vasopressor
modulates support)
proinflammatory phase to
return to homeostasis
 Suppression of adaptive
immunity
 Immune Response to Traumatic Injury
 Systemic response to severe injury
involves interactions across
 Hemostatic
 Inflammatory
 Endocrine
 Neurologic systems
 Different pathways ultimately lead
to endothelial cell activation
 Endothelium becomes more porous,
allowing humoral and cellular factors
to gain access to intercellular space
 Causes widespread tissue damage
-> Multiorgan failure
 Inflammatory Response to Injury
 Damage Associated Molecular
Patterns (DAMPs)
 Endogenous molecules produced
due to tissue damage or cellular
stress that interact with cell
receptors
 Systemic injury is sterile
 Pathogen Associated Molecular
Patterns (PAMPs)
 Non-self molecules exposed to
the immune system
 Signifies infection
 Inflammatory Response to Injury
 Damage Associated Molecular
Patterns (DAMPs)
 Released after tissue injury by
activated immune cells or from
necrotic cells
 Promote activation of innate
immune cells and recruit/activate
APCs (for host defense)
 Activate complement -> C3a, C5a
 Ultimately triggers release of
interleukins (inflammatory
mediators) -> SIRS
CNS Regulation of Inflammation in
Response to Injury
 Reflex Inhibition of Inflammation
 CNS receives information of injury-
induced inflammation via soluble
mediators and direct neural projections
 In turn, the CNS relays opposing anti-
inflammatory signals to the site of
inflammation to reduce inflammatory
mediator release by immunocytes
 Hormone release (ACTH, glucocorticoids)
 Sympathetic and parasympathetic
response
 Regulates HR, BP, RR, GI motility, Body
temp
 Vagal response induces Ach release to
curtail inflammatory response at injury site
 Afferent Signals to the Brain
 The CNS receives immunologic input from both the circulation and neural pathways
 Areas of the CNS devoid of BBB admit the passage of inflammatory mediators and
DAMPs
 Through fenestrated endothelium of the circumventricular organs
 Through a leaky BBB following traumatic brain injury
 Inflammatory stimuli can interact with receptors located on brain endothelial cells to
stimulate the release of proinflammatory mediators
 This route of inflammatory signaling in the CNS results in behavioral changes, such
as increased sleep, lethargy, reduced appetite, and fever
 Tissue injury can also be signaled to the brain via afferent neural fibers, specifically
that of the vagus nerve, which is part of the “inflammatory reflex”
 Cholinergic Anti-Inflammatory
Pathways
 Parasympathetic signaling
pathway – reflex inhibition of
inflammation
 Acetylcholine – primary
neurotransmitter of the
parasympathetic system,
reduces tissue macrophage
activation
 Cholinergic stimulation
directly reduces tissue
macrophage release of the
proinflammatory mediators
Neuroendocrine Response to Injury
 Injury activates a neuroendocrine
response from the brain
 Enhance immune defense
 Rapid mobilization of substrates
for energy
 Two principle pathways:
 Hypothalamic-pituitary-adrenal
(HPA) axis – release of
glucocorticoid hormones
 Sympathetic nervous system -
release of catecholamines
(epinephrine, norepinephrine)
 Adrenocorticotropic Hormone (ACTH)
 Synthesized and released by anterior pituitary

 Regulated by circadian signals

 Greatest elevation of ACTH occurs late at night until the hours
immediately before sunrise (in healthy humans)
 Pattern is altered in the injured subject

 Injuries are usually characterized by elevations in corticotropin-

releasing hormone and ACTH
 Adrenocorticotropic Hormone (ACTH)
 Mediators of ACTH release in the injured patient
 Proinflammatory cytokines
 Pain
 Anxiety
 Vasopressin
 Angiotensin II
 CCK
 Vasoactive intestinal polypeptide (VIP)
 Catecholamines
 Cholesterol

ACTH

Pregnenolone

Progesterone 17-α-OH-
pregnenolone

Dehydroepiandroster
11 – deoxycorticosterone 17 – α – OH – progesterone one

Corticosterone 11 – deoxycortisol Androstenedione

Aldosterone Cortisol Testosterone

MINERALOCORTICOID GLUCOCORTICOID Estradiol

SEX STEROIDS
 Cortisol Growth Hormone IGF-1 Epinephrine Insulin
-Major glucocorticoid in -Produced by Liver: protein -Prepares the body for -Exerts an anabolic
humans pituitary gland synthesis, the “fight or flight” effect
glycogenesis response (effect on • Hepatic glycogenesis
-Essential for survival -Promotes protein Adipose: glucose cardiovascular and and glycolysis
during physiologic synthesis and uptake, lipid pulmonary systems, • Peripheral glucose
uptake
stress, elevated after insulin resistance utilization metabolism)
• Lipogenesis
injury while enhancing Skeletal muscles: • Protein synthesis
the mobilization of glucose uptake, -Inhibited by hormones
fat stores protein synthesis and inflammatory
mediators associated
with stress response
-Potentiates the -Directly interacts -Promotes -Glycogenolysis, -Hyperglycemia and
actions of glucagon with GH receptors incorporation of gluconeogenesis, insulin resistance are
and epinephrine and enhances sulfate and lipolysis, ketogenesis hallmarks of injury and
hepatic synthesis proteoglycans into critical illness due to
-Favors of IGF-1 cartilage for the catabolic effects of
gluconeogenesis, skeletal growth -Decreased insulin circulating mediators
protein degradation, secretion, increased
lipolysis during injury glucagon secretion
Glucocorticoid receptor -GH enhances Aldosterone Stress hyperglycemia -Alters leukocyte
(cytosolic) phagocytic activity -Maintains • Adipose: Lipolysis
functions, decreases
• Inhibit transcription of immunocytes intravascular phagocytosis,
factors of genes of and increases • Skeletal muscle: chemotaxis, adhesion,
proinflammatory volume via Na+ Insulin resistance
proliferation of T retention in and respiratory burst
cytokines
cell populations exchange for K+ -Enhances leukocyte activities
• Promote expression of
anti-inflammatory and H+ in the early demargination with
 Glucocorticoids have been employed as effective
immunosuppressive agents
 Immunologic changes associated with glucocorticoid
administration
 Thymic involution
 Depressed cell mediated immune responses (decreases in T-killer and
natural killer cell functions)
 T-lymphocyte blastogenesis
 Mixed lymphocyte responsiveness
 Delayed hypersensitivity responses
 Monocytes lose capacity for intracellular killing but appear to maintain
chemotactic and phagocytic properties
 Neutrophils: Inhibit intracellular superoxide reactivity, suppress chemotaxis
and normalize apoptosis signaling mechanisms; Phagocytosis function is
unchanged
 Acute adrenal insufficiency (AAI)
 A life-threatening complication often seen in acutely ill patients with
adrenal suppression from exogenously administered glucocorticoids
with consequent atrophy of the adrenal glands
 Clinically, these patients present with weakness, nausea, vomiting,
fever and hypotension
 Objective findings include hypoglycemia from decreased
gluconeogenesis, hyponatremia from impaired renal tubular sodium
resorption and hyperkalemia from diminished kaliuresis
 Insufficient mineralocorticoid (aldosterone) activity also contributes
to hyponatremia and hyperkalemia
 Cortisol Growth Hormone IGF-1 Epinephrine Insulin
-Major glucocorticoid in -Produced by Liver: protein -Prepares the body for the -Exerts an anabolic
humans pituitary gland synthesis, “fight or flight” response effect
glycogenesis (effect on cardiovascular • Hepatic glycogenesis
-Essential for survival -Promotes protein Adipose: glucose and pulmonary systems, and glycolysis
during physiologic synthesis and uptake, lipid metabolism) • Peripheral glucose
stress, elevated after insulin resistance utilization uptake
injury while enhancing the Skeletal muscles: • Lipogenesis
mobilization of fat glucose uptake, • Protein synthesis
stores protein synthesis -Inhibited by hormones
and inflammatory
mediators associated
with stress response
-Potentiates the actions -Directly interacts -Promotes -Glycogenolysis, -Hyperglycemia and
of glucagon and with GH receptors incorporation of gluconeogenesis, insulin resistance are
epinephrine and enhances sulfate and lipolysis, ketogenesis hallmarks of injury and
hepatic synthesis of proteoglycans into critical illness due to the
-Favors IGF-1 cartilage for skeletal catabolic effects of
gluconeogenesis, growth -Decreased insulin circulating mediators
protein degradation, secretion, increased
lipolysis during injury glucagon secretion
Glucocorticoid receptor -GH enhances Aldosterone Stress hyperglycemia -Systemic insulin
(cytosolic) phagocytic activity -Maintains resistance likely results
• Adipose: Lipolysis
• Inhibit transcription of immunocytes and intravascular from pro-inflammatory
factors of genes of increases • Skeletal muscle: signals, which modulate
proinflammatory
volume via Na+
proliferation of T retention in Insulin resistance phosphorylation of the
cytokines cell populations insulin receptor
• Promote expression of exchange for K+ -Enhances leukocyte
and H+ in the early -Insulin release is
anti-inflammatory demargination with
DCT of the nephrons decreased mainly
genes resultant neutrophilia and
through activation of α-
 Cortisol Growth Hormone IGF-1 Epinephrine Insulin
-Major glucocorticoid in -Produced by Liver: protein -Prepares the body for the -Exerts an anabolic
humans pituitary gland synthesis, “fight or flight” response effect
glycogenesis (effect on cardiovascular • Hepatic glycogenesis
-Essential for survival -Promotes protein Adipose: glucose and pulmonary systems, and glycolysis
during physiologic synthesis and uptake, lipid metabolism) • Peripheral glucose
stress, elevated after insulin resistance utilization uptake
injury while enhancing the Skeletal muscles: • Lipogenesis
mobilization of fat glucose uptake, • Protein synthesis
stores protein synthesis -Inhibited by hormones
and inflammatory
mediators associated
with stress response
-Potentiates the actions -Directly interacts -Promotes -Glycogenolysis, -Hyperglycemia and
of glucagon and with GH receptors incorporation of gluconeogenesis, insulin resistance are
epinephrine and enhances sulfate and lipolysis, ketogenesis hallmarks of injury and
hepatic synthesis of proteoglycans into critical illness due to the
-Favors IGF-1 cartilage for skeletal catabolic effects of
gluconeogenesis, growth -Decreased insulin circulating mediators
protein degradation, secretion, increased
lipolysis during injury glucagon secretion
Glucocorticoid receptor -GH enhances Aldosterone Stress hyperglycemia -Systemic insulin
(cytosolic) phagocytic activity -Maintains resistance likely results
• Adipose: Lipolysis
• Inhibit transcription of immunocytes and intravascular from pro-inflammatory
factors of genes of increases • Skeletal muscle: signals, which modulate
proinflammatory
volume via Na+
proliferation of T retention in Insulin resistance phosphorylation of the
cytokines cell populations insulin receptor
• Promote expression of exchange for K+ -Enhances leukocyte
and H+ in the early -Insulin release is
anti-inflammatory demargination with
DCT of the nephrons decreased mainly
genes resultant neutrophilia and
through activation of α-
 Cortisol Growth Hormone IGF-1 Epinephrine Insulin
-Major glucocorticoid in -Produced by Liver: protein -Prepares the body for the -Exerts an anabolic
humans pituitary gland synthesis, “fight or flight” response effect
glycogenesis (effect on cardiovascular • Hepatic glycogenesis
-Essential for survival -Promotes protein Adipose: glucose and pulmonary systems, and glycolysis
during physiologic synthesis and uptake, lipid metabolism) • Peripheral glucose
stress, elevated after insulin resistance utilization uptake
injury while enhancing the Skeletal muscles: • Lipogenesis
mobilization of fat glucose uptake, • Protein synthesis
stores protein synthesis -Inhibited by hormones
and inflammatory
mediators associated
with stress response
-Potentiates the actions -Directly interacts -Promotes -Glycogenolysis, -Hyperglycemia and
of glucagon and with GH receptors incorporation of gluconeogenesis, insulin resistance are
epinephrine and enhances sulfate and lipolysis, ketogenesis hallmarks of injury and
hepatic synthesis of proteoglycans into critical illness due to the
-Favors IGF-1 cartilage for skeletal catabolic effects of
gluconeogenesis, growth -Decreased insulin circulating mediators
protein degradation, secretion, increased
lipolysis during injury glucagon secretion
Glucocorticoid receptor -GH enhances Aldosterone Stress hyperglycemia -Systemic insulin
(cytosolic) phagocytic activity -Maintains resistance likely results
• Adipose: Lipolysis
• Inhibit transcription of immunocytes and intravascular from pro-inflammatory
factors of genes of increases • Skeletal muscle: signals, which modulate
proinflammatory
volume via Na+
proliferation of T retention in Insulin resistance phosphorylation of the
cytokines cell populations insulin receptor
• Promote expression of exchange for K+ -Enhances leukocyte
and H+ in the early -Insulin release is
anti-inflammatory demargination with
DCT of the nephrons decreased mainly
genes resultant neutrophilia and
through activation of α-
 Cortisol Growth Hormone IGF-1 Epinephrine Insulin
-Major glucocorticoid in -Produced by Liver: protein -Prepares the body for the -Exerts an anabolic
humans pituitary gland synthesis, “fight or flight” response effect
glycogenesis (effect on cardiovascular • Hepatic glycogenesis
-Essential for survival -Promotes protein Adipose: glucose and pulmonary systems, and glycolysis
during physiologic synthesis and uptake, lipid metabolism) • Peripheral glucose
stress, elevated after insulin resistance utilization uptake
injury while enhancing the Skeletal muscles: • Lipogenesis
mobilization of fat glucose uptake, • Protein synthesis
stores protein synthesis -Inhibited by hormones
and inflammatory
mediators associated
with stress response
-Potentiates the actions -Directly interacts -Promotes -Glycogenolysis, -Hyperglycemia and
of glucagon and with GH receptors incorporation of gluconeogenesis, insulin resistance are
epinephrine and enhances sulfate and lipolysis, ketogenesis hallmarks of injury and
hepatic synthesis of proteoglycans into critical illness due to the
-Favors IGF-1 cartilage for skeletal catabolic effects of
gluconeogenesis, growth -Decreased insulin circulating mediators
protein degradation, secretion, increased
lipolysis during injury glucagon secretion
Glucocorticoid receptor -GH enhances Aldosterone Stress hyperglycemia -Systemic insulin
(cytosolic) phagocytic activity -Maintains resistance likely results
• Adipose: Lipolysis
• Inhibit transcription of immunocytes and intravascular from pro-inflammatory
factors of genes of increases • Skeletal muscle: signals, which modulate
proinflammatory
volume via Na+
proliferation of T retention in Insulin resistance phosphorylation of the
cytokines cell populations insulin receptor
• Promote expression of exchange for K+ -Enhances leukocyte
and H+ in the early -Insulin release is
anti-inflammatory demargination with
DCT of the nephrons decreased mainly
genes resultant neutrophilia and
through activation of α-
 Cortisol Growth Hormone IGF-1 Epinephrine Insulin
-Major glucocorticoid in -Produced by Liver: protein -Prepares the body for the -Exerts an anabolic
humans pituitary gland synthesis, “fight or flight” response effect
glycogenesis (effect on cardiovascular • Hepatic glycogenesis
-Essential for survival -Promotes protein Adipose: glucose and pulmonary systems, and glycolysis
during physiologic synthesis and uptake, lipid metabolism) • Peripheral glucose
stress, elevated after insulin resistance utilization uptake
injury while enhancing the Skeletal muscles: • Lipogenesis
mobilization of fat glucose uptake, • Protein synthesis
stores protein synthesis -Inhibited by hormones
and inflammatory
mediators associated
with stress response
-Potentiates the actions -Directly interacts -Promotes -Glycogenolysis, -Hyperglycemia and
of glucagon and with GH receptors incorporation of gluconeogenesis, insulin resistance are
epinephrine and enhances sulfate and lipolysis, ketogenesis hallmarks of injury and
hepatic synthesis of proteoglycans into critical illness due to the
-Favors IGF-1 cartilage for skeletal catabolic effects of
gluconeogenesis, growth -Decreased insulin circulating mediators
protein degradation, secretion, increased
lipolysis during injury glucagon secretion
Glucocorticoid receptor -GH enhances Aldosterone Stress hyperglycemia -Systemic insulin
(cytosolic) phagocytic activity -Maintains resistance likely results
• Adipose: Lipolysis
• Inhibit transcription of immunocytes and intravascular from pro-inflammatory
factors of genes of increases • Skeletal muscle: signals, which modulate
proinflammatory
volume via Na+
proliferation of T retention in Insulin resistance phosphorylation of the
cytokines cell populations insulin receptor
• Promote expression of exchange for K+ -Enhances leukocyte
and H+ in the early -Insulin release is
anti-inflammatory demargination with
DCT of the nephrons decreased mainly
genes resultant neutrophilia and
through activation of α-
 2 phases of insulin resistance in the
injured patient
1. Suppresses overall insulin release and occurs within a few hours after injury

2. Return to normal or excessive insulin production, but with persistent

hyperglycemia, consistent with peripheral resistance to insulin
Mediators of Inflammation
 Cytokines
 Protein signaling compounds essential for innate and adaptive immune
responses
 Mediate eradication of microorganisms and promote wound healing at the site
of local injury
 Pro-inflammatory cytokine response can become exaggerated causing
hemodynamic instability (septic shock) and metabolic derangements (muscle
wasting)
 Anti-inflammatory cytokines are also released to counteract this exaggerated
response
 But these mediators can also result in immunocyte dysfunction and host
immunosuppression
TNF- Among earliest responders after injury; half-life <20 min; activates TNF receptors 1 and 2; induces significant shock and
alpha catabolism
IL-1 Two forms (IL-1 α and IL-1 β); similar physiologic effects as TNF; induces fevers through prostaglandin activity in anterior
hypothalamus; promotes β-endorphin release from pituitary; half-life <6 min
IL-2 Promotes lymphocyte proliferation, immunoglobulin production, gut barrier integrity; half-life <10 min; attenuated
production after major blood loss leads to immunocompromise; regulates lymphocyte apoptosis
IL-4 Induces B-lymphocyte production of IgG4 and IgE, mediators of allergic and anthelmintic response; downregulates TNF,
IL-1, IL-6, IL-8
IL-5 Promotes eosinophil proliferation and airway inflammation
Il-6 Elicited by virtually all immunogenic cells; long half-life; circulating levels proportional to injury severity; prolongs
activated neutrophil survival
IL-8 Chemoattractant for neutrophils, basophils, eosinophils, lymphocytes
IL-10 Prominent anti-inflammatory cytokine; reduces mortality in animal sepsis and ARDS models
IL-12 Promotes Th1 differentiation; synergistic activity with IL-2
IL-13 Promotes B-lymphocyte function; structurally similar to IL-4; inhibits nitric oxide and endothelial activation
IL-15 Anti-inflammatory effect; promotes lymphocyte activation; promotes neutrophil phagocytosis in fungal infections
IL-18 Similar to IL-12 in function; levels elevated in sepsis, particularly gram-positive infections; high levels found in cardiac
deaths
IFN-γ Mediates IL-12 and IL-18 function; half-life of days; found in wounds 5–7 d after injury; promotes ARDS
GM-CSF Promotes wound healing and inflammation through activation of leukocytes
IL-21 Preferentially secreted by Th2 cells; structurally similar to IL-2 and IL-15; activates NK cells, B and T lymphocytes;
influences adaptive immunity
HMGB1 High mobility group box chromosomal protein; DNA transcription factor; late (downstream) mediator of inflammation
TNF- Among earliest responders after injury; half-life <20 min; activates TNF receptors 1 and 2; induces significant shock and
alpha catabolism
IL-1 Two forms (IL-1 α and IL-1 β); similar physiologic effects as TNF; induces fevers through prostaglandin activity in anterior
hypothalamus; promotes β-endorphin release from pituitary; half-life <6 min
IL-2 Promotes lymphocyte proliferation, immunoglobulin production, gut barrier integrity; half-life <10 min; attenuated
production after major blood loss leads to immunocompromise; regulates lymphocyte apoptosis
IL-4 Induces B-lymphocyte production of IgG4 and IgE, mediators of allergic and anthelmintic response; downregulates TNF,
IL-1, IL-6, IL-8
IL-5 Promotes eosinophil proliferation and airway inflammation
Il-6 Elicited by virtually all immunogenic cells; long half-life; circulating levels proportional to injury severity; prolongs
activated neutrophil survival
IL-8 Chemoattractant for neutrophils, basophils, eosinophils, lymphocytes
IL-10 Prominent anti-inflammatory cytokine; reduces mortality in animal sepsis and ARDS models
IL-12 Promotes Th1 differentiation; synergistic activity with IL-2
IL-13 Promotes B-lymphocyte function; structurally similar to IL-4; inhibits nitric oxide and endothelial activation
IL-15 Anti-inflammatory effect; promotes lymphocyte activation; promotes neutrophil phagocytosis in fungal infections
IL-18 Similar to IL-12 in function; levels elevated in sepsis, particularly gram-positive infections; high levels found in cardiac
deaths
IFN-γ Mediates IL-12 and IL-18 function; half-life of days; found in wounds 5–7 d after injury; promotes ARDS
GM-CSF Promotes wound healing and inflammation through activation of leukocytes
IL-21 Preferentially secreted by Th2 cells; structurally similar to IL-2 and IL-15; activates NK cells, B and T lymphocytes;
influences adaptive immunity
HMGB1 High mobility group box chromosomal protein; DNA transcription factor; late (downstream) mediator of inflammation
TNF- Among earliest responders after injury; half-life <20 min; activates TNF receptors 1 and 2; induces significant shock and
alpha catabolism
IL-1 Two forms (IL-1 α and IL-1 β); similar physiologic effects as TNF; induces fevers through prostaglandin activity in anterior
hypothalamus; promotes β-endorphin release from pituitary; half-life <6 min
IL-2 Promotes lymphocyte proliferation, immunoglobulin production, gut barrier integrity; half-life <10 min; attenuated
production after major blood loss leads to immunocompromise; regulates lymphocyte apoptosis
IL-4 Induces B-lymphocyte production of IgG4 and IgE, mediators of allergic and anthelmintic response; downregulates TNF,
IL-1, IL-6, IL-8
IL-5 Promotes eosinophil proliferation and airway inflammation
Il-6 Elicited by virtually all immunogenic cells; long half-life; circulating levels proportional to injury severity; prolongs
activated neutrophil survival
IL-8 Chemoattractant for neutrophils, basophils, eosinophils, lymphocytes
IL-10 Prominent anti-inflammatory cytokine; reduces mortality in animal sepsis and ARDS models
IL-12 Promotes Th1 differentiation; synergistic activity with IL-2
IL-13 Promotes B-lymphocyte function; structurally similar to IL-4; inhibits nitric oxide and endothelial activation
IL-15 Anti-inflammatory effect; promotes lymphocyte activation; promotes neutrophil phagocytosis in fungal infections
IL-18 Similar to IL-12 in function; levels elevated in sepsis, particularly gram-positive infections; high levels found in cardiac
deaths
IFN-γ Mediates IL-12 and IL-18 function; half-life of days; found in wounds 5–7 d after injury; promotes ARDS
GM-CSF Promotes wound healing and inflammation through activation of leukocytes
IL-21 Preferentially secreted by Th2 cells; structurally similar to IL-2 and IL-15; activates NK cells, B and T lymphocytes;
influences adaptive immunity
HMGB1 High mobility group box chromosomal protein; DNA transcription factor; late (downstream) mediator of inflammation
TNF- Among earliest responders after injury; half-life <20 min; activates TNF receptors 1 and 2; induces significant shock and
alpha catabolism
IL-1 Two forms (IL-1 α and IL-1 β); similar physiologic effects as TNF; induces fevers through prostaglandin activity in anterior
hypothalamus; promotes β-endorphin release from pituitary; half-life <6 min
IL-2 Promotes lymphocyte proliferation, immunoglobulin production, gut barrier integrity; half-life <10 min; attenuated
production after major blood loss leads to immunocompromise; regulates lymphocyte apoptosis
IL-4 Induces B-lymphocyte production of IgG4 and IgE, mediators of allergic and anthelmintic response; downregulates TNF,
IL-1, IL-6, IL-8
IL-5 Promotes eosinophil proliferation and airway inflammation
Il-6 Elicited by virtually all immunogenic cells; long half-life; circulating levels proportional to injury severity; prolongs
activated neutrophil survival
IL-8 Chemoattractant for neutrophils, basophils, eosinophils, lymphocytes
IL-10 Prominent anti-inflammatory cytokine; reduces mortality in animal sepsis and ARDS models
IL-12 Promotes Th1 differentiation; synergistic activity with IL-2
IL-13 Promotes B-lymphocyte function; structurally similar to IL-4; inhibits nitric oxide and endothelial activation
IL-15 Anti-inflammatory effect; promotes lymphocyte activation; promotes neutrophil phagocytosis in fungal infections
IL-18 Similar to IL-12 in function; levels elevated in sepsis, particularly gram-positive infections; high levels found in cardiac
deaths
IFN-γ Mediates IL-12 and IL-18 function; half-life of days; found in wounds 5–7 d after injury; promotes ARDS
GM-CSF Promotes wound healing and inflammation through activation of leukocytes
IL-21 Preferentially secreted by Th2 cells; structurally similar to IL-2 and IL-15; activates NK cells, B and T lymphocytes;
influences adaptive immunity
HMGB1 High mobility group box chromosomal protein; DNA transcription factor; late (downstream) mediator of inflammation
TNF- Among earliest responders after injury; half-life <20 min; activates TNF receptors 1 and 2; induces significant shock and
alpha catabolism
IL-1 Two forms (IL-1 α and IL-1 β); similar physiologic effects as TNF; induces fevers through prostaglandin activity in anterior
hypothalamus; promotes β-endorphin release from pituitary; half-life <6 min
IL-2 Promotes lymphocyte proliferation, immunoglobulin production, gut barrier integrity; half-life <10 min; attenuated
production after major blood loss leads to immunocompromise; regulates lymphocyte apoptosis
IL-4 Induces B-lymphocyte production of IgG4 and IgE, mediators of allergic and anthelmintic response; downregulates TNF,
IL-1, IL-6, IL-8
IL-5 Promotes eosinophil proliferation and airway inflammation
Il-6 Elicited by virtually all immunogenic cells; long half-life; circulating levels proportional to injury severity; prolongs
activated neutrophil survival
IL-8 Chemoattractant for neutrophils, basophils, eosinophils, lymphocytes
IL-10 Prominent anti-inflammatory cytokine; reduces mortality in animal sepsis and ARDS models
IL-12 Promotes Th1 differentiation; synergistic activity with IL-2
IL-13 Promotes B-lymphocyte function; structurally similar to IL-4; inhibits nitric oxide and endothelial activation
IL-15 Anti-inflammatory effect; promotes lymphocyte activation; promotes neutrophil phagocytosis in fungal infections
IL-18 Similar to IL-12 in function; levels elevated in sepsis, particularly gram-positive infections; high levels found in cardiac
deaths
IFN-γ Mediates IL-12 and IL-18 function; half-life of days; found in wounds 5–7 d after injury; promotes ARDS
GM-CSF Promotes wound healing and inflammation through activation of leukocytes
IL-21 Preferentially secreted by Th2 cells; structurally similar to IL-2 and IL-15; activates NK cells, B and T lymphocytes;
influences adaptive immunity
HMGB1 High mobility group box chromosomal protein; DNA transcription factor; late (downstream) mediator of inflammation
TNF- Among earliest responders after injury; half-life <20 min; activates TNF receptors 1 and 2; induces significant shock and
alpha catabolism
IL-1 Two forms (IL-1 α and IL-1 β); similar physiologic effects as TNF; induces fevers through prostaglandin activity in anterior
hypothalamus; promotes β-endorphin release from pituitary; half-life <6 min
IL-2 Promotes lymphocyte proliferation, immunoglobulin production, gut barrier integrity; half-life <10 min; attenuated
production after major blood loss leads to immunocompromise; regulates lymphocyte apoptosis
IL-4 Induces B-lymphocyte production of IgG4 and IgE, mediators of allergic and anthelmintic response; downregulates TNF,
IL-1, IL-6, IL-8
IL-5 Promotes eosinophil proliferation and airway inflammation
Il-6 Elicited by virtually all immunogenic cells; long half-life; circulating levels proportional to injury severity; prolongs
activated neutrophil survival
IL-8 Chemoattractant for neutrophils, basophils, eosinophils, lymphocytes
IL-10 Prominent anti-inflammatory cytokine; reduces mortality in animal sepsis and ARDS models
IL-12 Promotes Th1 differentiation; synergistic activity with IL-2
IL-13 Promotes B-lymphocyte function; structurally similar to IL-4; inhibits nitric oxide and endothelial activation
IL-15 Anti-inflammatory effect; promotes lymphocyte activation; promotes neutrophil phagocytosis in fungal infections
IL-18 Similar to IL-12 in function; levels elevated in sepsis, particularly gram-positive infections; high levels found in cardiac
deaths
IFN-γ Mediates IL-12 and IL-18 function; half-life of days; found in wounds 5–7 d after injury; promotes ARDS
GM-CSF Promotes wound healing and inflammation through activation of leukocytes
IL-21 Preferentially secreted by Th2 cells; structurally similar to IL-2 and IL-15; activates NK cells, B and T lymphocytes;
influences adaptive immunity
HMGB1 High mobility group box chromosomal protein; DNA transcription factor; late (downstream) mediator of inflammation
TNF- Among earliest responders after injury; half-life <20 min; activates TNF receptors 1 and 2; induces significant shock and
alpha catabolism
IL-1 Two forms (IL-1 α and IL-1 β); similar physiologic effects as TNF; induces fevers through prostaglandin activity in anterior
hypothalamus; promotes β-endorphin release from pituitary; half-life <6 min
IL-2 Promotes lymphocyte proliferation, immunoglobulin production, gut barrier integrity; half-life <10 min; attenuated
production after major blood loss leads to immunocompromise; regulates lymphocyte apoptosis
IL-4 Induces B-lymphocyte production of IgG4 and IgE, mediators of allergic and anthelmintic response; downregulates TNF,
IL-1, IL-6, IL-8
IL-5 Promotes eosinophil proliferation and airway inflammation
Il-6 Elicited by virtually all immunogenic cells; long half-life; circulating levels proportional to injury severity; prolongs
activated neutrophil survival
IL-8 Chemoattractant for neutrophils, basophils, eosinophils, lymphocytes
IL-10 Prominent anti-inflammatory cytokine; reduces mortality in animal sepsis and ARDS models
IL-12 Promotes Th1 differentiation; synergistic activity with IL-2
IL-13 Promotes B-lymphocyte function; structurally similar to IL-4; inhibits nitric oxide and endothelial activation
IL-15 Anti-inflammatory effect; promotes lymphocyte activation; promotes neutrophil phagocytosis in fungal infections
IL-18 Similar to IL-12 in function; levels elevated in sepsis, particularly gram-positive infections; high levels found in cardiac
deaths
IFN-γ Mediates IL-12 and IL-18 function; half-life of days; found in wounds 5–7 d after injury; promotes ARDS
GM-CSF Promotes wound healing and inflammation through activation of leukocytes
IL-21 Preferentially secreted by Th2 cells; structurally similar to IL-2 and IL-15; activates NK cells, B and T lymphocytes;
influences adaptive immunity
HMGB1 High mobility group box chromosomal protein; DNA transcription factor; late (downstream) mediator of inflammation
TNF- Among earliest responders after injury; half-life <20 min; activates TNF receptors 1 and 2; induces significant shock and
alpha catabolism
IL-1 Two forms (IL-1 α and IL-1 β); similar physiologic effects as TNF; induces fevers through prostaglandin activity in anterior
hypothalamus; promotes β-endorphin release from pituitary; half-life <6 min
IL-2 Promotes lymphocyte proliferation, immunoglobulin production, gut barrier integrity; half-life <10 min; attenuated
production after major blood loss leads to immunocompromise; regulates lymphocyte apoptosis
IL-4 Induces B-lymphocyte production of IgG4 and IgE, mediators of allergic and anthelmintic response; downregulates TNF,
IL-1, IL-6, IL-8
IL-5 Promotes eosinophil proliferation and airway inflammation
Il-6 Elicited by virtually all immunogenic cells; long half-life; circulating levels proportional to injury severity; prolongs
activated neutrophil survival
IL-8 Chemoattractant for neutrophils, basophils, eosinophils, lymphocytes
IL-10 Prominent anti-inflammatory cytokine; reduces mortality in animal sepsis and ARDS models
IL-12 Promotes Th1 differentiation; synergistic activity with IL-2
IL-13 Promotes B-lymphocyte function; structurally similar to IL-4; inhibits nitric oxide and endothelial activation
IL-15 Anti-inflammatory effect; promotes lymphocyte activation; promotes neutrophil phagocytosis in fungal infections
IL-18 Similar to IL-12 in function; levels elevated in sepsis, particularly gram-positive infections; high levels found in cardiac
deaths
IFN-γ Mediates IL-12 and IL-18 function; half-life of days; found in wounds 5–7 d after injury; promotes ARDS
GM-CSF Promotes wound healing and inflammation through activation of leukocytes
IL-21 Preferentially secreted by Th2 cells; structurally similar to IL-2 and IL-15; activates NK cells, B and T lymphocytes;
influences adaptive immunity
HMGB1 High mobility group box chromosomal protein; DNA transcription factor; late (downstream) mediator of inflammation
TNF- Among earliest responders after injury; half-life <20 min; activates TNF receptors 1 and 2; induces significant shock and
alpha catabolism
IL-1 Two forms (IL-1 α and IL-1 β); similar physiologic effects as TNF; induces fevers through prostaglandin activity in anterior
hypothalamus; promotes β-endorphin release from pituitary; half-life <6 min
IL-2 Promotes lymphocyte proliferation, immunoglobulin production, gut barrier integrity; half-life <10 min; attenuated
production after major blood loss leads to immunocompromise; regulates lymphocyte apoptosis
IL-4 Induces B-lymphocyte production of IgG4 and IgE, mediators of allergic and anthelmintic response; downregulates TNF,
IL-1, IL-6, IL-8
IL-5 Promotes eosinophil proliferation and airway inflammation
Il-6 Elicited by virtually all immunogenic cells; long half-life; circulating levels proportional to injury severity; prolongs
activated neutrophil survival
IL-8 Chemoattractant for neutrophils, basophils, eosinophils, lymphocytes
IL-10 Prominent anti-inflammatory cytokine; reduces mortality in animal sepsis and ARDS models
IL-12 Promotes Th1 differentiation; synergistic activity with IL-2
IL-13 Promotes B-lymphocyte function; structurally similar to IL-4; inhibits nitric oxide and endothelial activation
IL-15 Anti-inflammatory effect; promotes lymphocyte activation; promotes neutrophil phagocytosis in fungal infections
IL-18 Similar to IL-12 in function; levels elevated in sepsis, particularly gram-positive infections; high levels found in cardiac
deaths
IFN-γ Mediates IL-12 and IL-18 function; half-life of days; found in wounds 5–7 d after injury; promotes ARDS
GM-CSF Promotes wound healing and inflammation through activation of leukocytes
IL-21 Preferentially secreted by Th2 cells; structurally similar to IL-2 and IL-15; activates NK cells, B and T lymphocytes;
influences adaptive immunity
HMGB1 High mobility group box chromosomal protein; DNA transcription factor; late (downstream) mediator of inflammation
TNF- Among earliest responders after injury; half-life <20 min; activates TNF receptors 1 and 2; induces significant shock and
alpha catabolism
IL-1 Two forms (IL-1 α and IL-1 β); similar physiologic effects as TNF; induces fevers through prostaglandin activity in anterior
hypothalamus; promotes β-endorphin release from pituitary; half-life <6 min
IL-2 Promotes lymphocyte proliferation, immunoglobulin production, gut barrier integrity; half-life <10 min; attenuated
production after major blood loss leads to immunocompromise; regulates lymphocyte apoptosis
IL-4 Induces B-lymphocyte production of IgG4 and IgE, mediators of allergic and anthelmintic response; downregulates TNF,
IL-1, IL-6, IL-8
IL-5 Promotes eosinophil proliferation and airway inflammation
Il-6 Elicited by virtually all immunogenic cells; long half-life; circulating levels proportional to injury severity; prolongs
activated neutrophil survival
IL-8 Chemoattractant for neutrophils, basophils, eosinophils, lymphocytes
IL-10 Prominent anti-inflammatory cytokine; reduces mortality in animal sepsis and ARDS models
IL-12 Promotes Th1 differentiation; synergistic activity with IL-2
IL-13 Promotes B-lymphocyte function; structurally similar to IL-4; inhibits nitric oxide and endothelial activation
IL-15 Anti-inflammatory effect; promotes lymphocyte activation; promotes neutrophil phagocytosis in fungal infections
IL-18 Similar to IL-12 in function; levels elevated in sepsis, particularly gram-positive infections; high levels found in cardiac
deaths
IFN-γ Mediates IL-12 and IL-18 function; half-life of days; found in wounds 5–7 d after injury; promotes ARDS
GM-CSF Promotes wound healing and inflammation through activation of leukocytes
IL-21 Preferentially secreted by Th2 cells; structurally similar to IL-2 and IL-15; activates NK cells, B and T lymphocytes;
influences adaptive immunity
HMGB1 High mobility group box chromosomal protein; DNA transcription factor; late (downstream) mediator of inflammation
TNF- Among earliest responders after injury; half-life <20 min; activates TNF receptors 1 and 2; induces significant shock and
alpha catabolism
IL-1 Two forms (IL-1 α and IL-1 β); similar physiologic effects as TNF; induces fevers through prostaglandin activity in anterior
hypothalamus; promotes β-endorphin release from pituitary; half-life <6 min
IL-2 Promotes lymphocyte proliferation, immunoglobulin production, gut barrier integrity; half-life <10 min; attenuated
production after major blood loss leads to immunocompromise; regulates lymphocyte apoptosis
IL-4 Induces B-lymphocyte production of IgG4 and IgE, mediators of allergic and anthelmintic response; downregulates TNF,
IL-1, IL-6, IL-8
IL-5 Promotes eosinophil proliferation and airway inflammation
Il-6 Elicited by virtually all immunogenic cells; long half-life; circulating levels proportional to injury severity; prolongs
activated neutrophil survival
IL-8 Chemoattractant for neutrophils, basophils, eosinophils, lymphocytes
IL-10 Prominent anti-inflammatory cytokine; reduces mortality in animal sepsis and ARDS models
IL-12 Promotes Th1 differentiation; synergistic activity with IL-2
IL-13 Promotes B-lymphocyte function; structurally similar to IL-4; inhibits nitric oxide and endothelial activation
IL-15 Anti-inflammatory effect; promotes lymphocyte activation; promotes neutrophil phagocytosis in fungal infections
IL-18 Similar to IL-12 in function; levels elevated in sepsis, particularly gram-positive infections; high levels found in cardiac
deaths
IFN-γ Mediates IL-12 and IL-18 function; half-life of days; found in wounds 5–7 d after injury; promotes ARDS
GM-CSF Promotes wound healing and inflammation through activation of leukocytes
IL-21 Preferentially secreted by Th2 cells; structurally similar to IL-2 and IL-15; activates NK cells, B and T lymphocytes;
influences adaptive immunity
HMGB1 High mobility group box chromosomal protein; DNA transcription factor; late (downstream) mediator of inflammation
TNF- Among earliest responders after injury; half-life <20 min; activates TNF receptors 1 and 2; induces significant shock and
alpha catabolism
IL-1 Two forms (IL-1 α and IL-1 β); similar physiologic effects as TNF; induces fevers through prostaglandin activity in anterior
hypothalamus; promotes β-endorphin release from pituitary; half-life <6 min
IL-2 Promotes lymphocyte proliferation, immunoglobulin production, gut barrier integrity; half-life <10 min; attenuated
production after major blood loss leads to immunocompromise; regulates lymphocyte apoptosis
IL-4 Induces B-lymphocyte production of IgG4 and IgE, mediators of allergic and anthelmintic response; downregulates TNF,
IL-1, IL-6, IL-8
IL-5 Promotes eosinophil proliferation and airway inflammation
Il-6 Elicited by virtually all immunogenic cells; long half-life; circulating levels proportional to injury severity; prolongs
activated neutrophil survival
IL-8 Chemoattractant for neutrophils, basophils, eosinophils, lymphocytes
IL-10 Prominent anti-inflammatory cytokine; reduces mortality in animal sepsis and ARDS models
IL-12 Promotes Th1 differentiation; synergistic activity with IL-2
IL-13 Promotes B-lymphocyte function; structurally similar to IL-4; inhibits nitric oxide and endothelial activation
IL-15 Anti-inflammatory effect; promotes lymphocyte activation; promotes neutrophil phagocytosis in fungal infections
IL-18 Similar to IL-12 in function; levels elevated in sepsis, particularly gram-positive infections; high levels found in cardiac
deaths
IFN-γ Mediates IL-12 and IL-18 function; half-life of days; found in wounds 5–7 d after injury; promotes ARDS
GM-CSF Promotes wound healing and inflammation through activation of leukocytes
IL-21 Preferentially secreted by Th2 cells; structurally similar to IL-2 and IL-15; activates NK cells, B and T lymphocytes;
influences adaptive immunity
HMGB1 High mobility group box chromosomal protein; DNA transcription factor; late (downstream) mediator of inflammation
TNF- Among earliest responders after injury; half-life <20 min; activates TNF receptors 1 and 2; induces significant shock and
alpha catabolism
IL-1 Two forms (IL-1 α and IL-1 β); similar physiologic effects as TNF; induces fevers through prostaglandin activity in anterior
hypothalamus; promotes β-endorphin release from pituitary; half-life <6 min
IL-2 Promotes lymphocyte proliferation, immunoglobulin production, gut barrier integrity; half-life <10 min; attenuated
production after major blood loss leads to immunocompromise; regulates lymphocyte apoptosis
IL-4 Induces B-lymphocyte production of IgG4 and IgE, mediators of allergic and anthelmintic response; downregulates TNF,
IL-1, IL-6, IL-8
IL-5 Promotes eosinophil proliferation and airway inflammation
Il-6 Elicited by virtually all immunogenic cells; long half-life; circulating levels proportional to injury severity; prolongs
activated neutrophil survival
IL-8 Chemoattractant for neutrophils, basophils, eosinophils, lymphocytes
IL-10 Prominent anti-inflammatory cytokine; reduces mortality in animal sepsis and ARDS models
IL-12 Promotes Th1 differentiation; synergistic activity with IL-2
IL-13 Promotes B-lymphocyte function; structurally similar to IL-4; inhibits nitric oxide and endothelial activation
IL-15 Anti-inflammatory effect; promotes lymphocyte activation; promotes neutrophil phagocytosis in fungal infections
IL-18 Similar to IL-12 in function; levels elevated in sepsis, particularly gram-positive infections; high levels found in cardiac
deaths
IFN-γ Mediates IL-12 and IL-18 function; half-life of days; found in wounds 5–7 d after injury; promotes ARDS
GM-CSF Promotes wound healing and inflammation through activation of leukocytes
IL-21 Preferentially secreted by Th2 cells; structurally similar to IL-2 and IL-15; activates NK cells, B and T lymphocytes;
influences adaptive immunity
HMGB1 High mobility group box chromosomal protein; DNA transcription factor; late (downstream) mediator of inflammation
TNF- Among earliest responders after injury; half-life <20 min; activates TNF receptors 1 and 2; induces significant shock and
alpha catabolism
IL-1 Two forms (IL-1 α and IL-1 β); similar physiologic effects as TNF; induces fevers through prostaglandin activity in anterior
hypothalamus; promotes β-endorphin release from pituitary; half-life <6 min
IL-2 Promotes lymphocyte proliferation, immunoglobulin production, gut barrier integrity; half-life <10 min; attenuated
production after major blood loss leads to immunocompromise; regulates lymphocyte apoptosis
IL-4 Induces B-lymphocyte production of IgG4 and IgE, mediators of allergic and anthelmintic response; downregulates TNF,
IL-1, IL-6, IL-8
IL-5 Promotes eosinophil proliferation and airway inflammation
Il-6 Elicited by virtually all immunogenic cells; long half-life; circulating levels proportional to injury severity; prolongs
activated neutrophil survival
IL-8 Chemoattractant for neutrophils, basophils, eosinophils, lymphocytes
IL-10 Prominent anti-inflammatory cytokine; reduces mortality in animal sepsis and ARDS models
IL-12 Promotes Th1 differentiation; synergistic activity with IL-2
IL-13 Promotes B-lymphocyte function; structurally similar to IL-4; inhibits nitric oxide and endothelial activation
IL-15 Anti-inflammatory effect; promotes lymphocyte activation; promotes neutrophil phagocytosis in fungal infections
IL-18 Similar to IL-12 in function; levels elevated in sepsis, particularly gram-positive infections; high levels found in cardiac
deaths
IFN-γ Mediates IL-12 and IL-18 function; half-life of days; found in wounds 5–7 d after injury; promotes ARDS
GM-CSF Promotes wound healing and inflammation through activation of leukocytes
IL-21 Preferentially secreted by Th2 cells; structurally similar to IL-2 and IL-15; activates NK cells, B and T lymphocytes;
influences adaptive immunity
HMGB1 High mobility group box chromosomal protein; DNA transcription factor; late (downstream) mediator of inflammation
 Cytokines act on their target cells
by binding to membrane
receptors
 Several receptors have
characteristic signaling pathways
associated with them
 JAK/STAT signaling pathway – Type
I/II cytokine receptors selectively
associated with Janus kinases
(JAK1, JAK2, JAK3, TYK2)
 Eicosanoids
 Derivatives of the membrane phospholipid arachidonic acid
 Secreted by virtually all nucleated cells except lymphocytes
 Generated either by the cyclooxygenase or lipoxygenase pathway

 Eicosanoids are not stored in cells but are synthesized rapidly upon stimulation by:
 Hypoxic injury
 Direct tissue injury

 Endotoxin

 NE

 Vasopressin

 Angiotensin II

 Bradykinin, serotonin

 Acetylcholine

 Cytokines

 Histamine
 Synthesis of Arachidonic Acid from
Phospholipase A2
PHOSPHOLIPID

Phospholipase A2 Corticosteroids

ARACHIDONIC ACID

Cyclooxygenase Lipooxygenase

Cyclic endoperoxidases HPETE

Prostaglandins Thromboxane A2 HETE Leukotrienes

 Complement

 Complement system is
activated following traumatic
injury
 Major effector of the innate
immune system
 3 pathways:
 Ultimately leads to C3a and C5a
generation (anaphylotoxins),
C3b generation (opsonin), C5b
(formation of membrane attack
complex)
 Kallikrein-Kinin System
 Kallikrein
 Prekallikrein: inactive form in plasma bound to
HMWK
 Stimuli lead to binding of prekallikrein-HMWK
complex to factor XII to initiate intrinsic clotting
cascade
 Bradykinins
 HMWK is cleaved by kallikrein to form
bradykinin
 Potent vasodilator
 Release is stimulated by hypoxic and ischemic
injury
 Bradykinin and kallikrein levels are increased
following hemorrhagic shock, sepsis, and
tissue injury
 Heat shock proteins – its release is stimulated by hypoxia, trauma, heavy metals,
local trauma and hemorrhage
 Reactive Oxygen Metabolites - cause tissue injury by oxidation of unsaturated
fatty acids within the cell membrane
 Serotonin – stimulates vasoconstriction, bronchoconstriction, platelet aggregation
 Histamine – increased levels during hemorrhagic shock trauma, thermal injury,
endotoxemia, sepsis
 Fatty acid metabolites (omega-3, omega-6) - precursors of inflammatory
mediators associated with injury and the stress response
 Leukotrienes
 Prostaglandin
 Platelet activating factor
 Cellular Response to Injury
1. Gene Expression and Regulation
 Protein synthesis can be regulated
at various stages to render these
molecules nonfunctional
 Transcription factors and
coactivators bind to specific DNA
sequences to mediate gene
expression
 Repressor sequences are non-
coding regions that bind protein to
inhibit gene expression
 Nuclear factor κB (NF-κB) –
transcription factor that regulates
gene products expressed after
inflammatory stimuli
2. Cell Signaling Pathways
 Heat Shock Proteins
 G-Protein Receptors
 Ligand- Gated Ion Channels
 Receptor Tyrosine Kinases
(JAK/STAT)
 Cell-Mediated Inflammatory Response
 Platelets - small circulating fragments of
megakaryocytes
 Lymphocytes and T-Cell Immunity –
involved in adaptive immune response
 Mast cells – located in tissues, releases
TNF leading to neutrophil recruitment
and pathogen clearance
 Monocytes - leukocytes from bone
marrow progenitors, circulate in
bloodstream, exit vasculature, and
differentiate into macrophages upon
migrating into appropriate tissues
 Neutrophils – first responders with short
half-lives (4-10 hrs)
 Endothelium Mediated Injury
 Neutrophil-Endothelium Interaction
 Nitric oxide
 Prostacyclin
 Endothelins
 Platelet Activating Factor
 Atrial Natriuretic Peptides
Surgical Metabolism
 Main source of fuel:
 Body fat
 Muscle protein
 More glycogen stores within
skeletal, cardiac, and smooth
muscle cells compared to liver
 Not readily available for
systemic use
 Hepatic glycogen stores are
depleted
 Fall in serum glucose within <16
hrs
 Glucagon, norepinephrine,
vasopressin, and angiotensin II
promote glycogenolysis during
fasting
 Epinephrine and cortisol promote
pyruvate shuttling to liver for
gluconeogenesis
 Precursors of hepatic
gluconeogenesis: lactate,
glycerol, alanine, glutamine
 Cori cycle provides 40% of
plasma glucose during starvation
 Due to insufficient lactate from
skeletal muscles, glucose-alanine
cycle is favored -> proteolysis
 Systemic proteolysis of 75g/day
 Urinary nitrogen excretion from 7-
10g/d -> 30g or more per day
 In prolonged starvation,
the vital organs adapt
to using ketones as
their main fuel source
 Systemic proteolysis of
20g/day
 Urinary nitrogen
excretion of 2-5g/day
 Mobilization of lipid
stores decreases rate of
glycolysis,
gluconeogenesis,
proteolysis, and overall
glucose requirement
 Main source of fuel: Lipid
 Adipose stores in the form of
triglycerides are the predominant
energy source (50 to 80%) during
critical illness and trauma
 Main stimulus of lipolysis is
catecholamine stimulus of
hormone-sensitive triglyceride
lipase
 Must be broken down into FFA and
glycerol
 Enhanced nitrogen loss
(catabolism)
 Magnitude of metabolic
expenditure is directly
proportional to severity of insult
 Lipid Absorption
 Oxidation of 1 g of fat = 9 kcal of energy
 Dietary and exogenous sources provide the
major source of triglycerides
 Dietary lipids are not readily absorbable in
the gut
 Pancreatic lipase and duodenal phopholipase
hydrolyze the triglycerides into FFA and
monoglycerides -> systemic absorption ->
resynthesis of triglyceride via fatty acyl-CoA ->
bound to chylomicrons and enter lymphatic
system (LCTs)
 Short chain triglycerides enter the portal system
and are transported to the liver by albumin carriers
 Lipolysis and Fatty Acid Oxidation
 FFA in the circulation are absorbed by cells
conjugated to acyl-CoA within the cytoplasm
 The transport of fatty acyl-CoA from the outer
mitochondrial membrane across the inner
mitochondrial membrane occurs via the
carnitine shuttle
 MCTs bypass the carnitine shuttle and readily cross
the inner mitochondrial membrane -> more readily
oxidized than LCTs
 In the mitochondria, fatty acyl-CoA undergoes β-
oxidation, and acetyl-CoA is produced with
each pass through the cycle
 Each acetyl-CoA enters TCA/Kreb’s cycle -> 12
ATP, CO2, H20
 Excess acetyl-CoA molecules serve as
precursors for ketogenesis
 Ketogenesis
 Increased lipolysis and reduced systemic CHO availability during starvation diverts
excess acetyl-CoA toward hepatic ketogenesis

 Ketosis represents a state in which hepatic ketone production exceeds extrahepatic

ketone utilization.

 The rate of ketogenesis appears to be inversely related to the severity of injury

 Major trauma, sever shock, and sepsis attenuate ketogenesis by increasing insulin
levels and by rapid tissue oxidation of FFA
 Carbohydrate Metabolism
 Oxidation of 1 gram of CHO = 4 kcal
 In starvation, glucose production occurs at the expense of protein stores
 Hence, the maintenance glucose administration in surgical patients serves
to minimize muscle wasting
 Exogenous administration of small amounts of glucose (~ 50g/d) facilitates
fat entry into the TCA cycle and reduces ketosis
 But in septic and trauma patients, there is still some degree of muscle wasting
-> due to effect of hormonal and proinflammatory mediators
 However, insulin administration can reverse protein catabolism during severe stress
(stimulates protein synthesis in skeletal muscles, inhibits hepatocyte protein
degradation)
 Injury and severe infections acutely induce a state of peripheral
glucose intolerance, despite ample insulin production
severalfold above baseline
 The increase in plasma glucose levels is proportional to the
severity of injury and this net hepatic gluconeogenic response
is believed to be under the influence of glucagon
 Shunting of glucose away from the nonessential organs such as
skeletal muscles and adipose tissues is mediated by
catecholamines
 Protein and Amino Acid Metabolism
 Every 6 grams of protein = ~1 gram nitrogen
 Degradation of 1 gram protein = 4 kcal
 Following injury, systemic proteolysis occurs -> urinary nitrogen
excretion increases >30g/d, and a loss in lean body mass of 1.5%
per day
 Accelerated urea excretion also causes excretion of intracellular
elements: sulfur, phosphorus, potassium, magnesium and
creatinine
 Net changes in protein
catabolism and synthesis
correspond to the severity and
duration of injury
 Elective operations and minor
injuries only have lower protein
synthesis and moderate
protein breakdown
 Severe trauma, burns and
sepsis cause increased protein
catabolism/breakdown
Nutrition in the Surgical Patient
 Estimating Energy Requirements

 Pertinent information is obtained by determining the presence of weight loss, chronic

illnesses or dietary habits that influence the quantity and quality of food intake
 Physical examination seeks to assess loss of the following reflecting frank or
impending nutritional deficiency
 Muscle tissues
 Adipose tissues
 Organ dysfunction
 Subtle changes in skin
 Hair
 Neuromuscular function
 Anthropometric data and biochemical determinations may be used to
substantiate the patient’s history and physical findings
 Weight change, skinfold thickness, and arm circumference muscle area
 Creatinine excretion, albumin level, prealbumin level, total lymphocyte
count, and transferrin level
 A fundamental goal of nutritional support is to meet the energy requirements
for metabolic processes, core temperature maintenance and tissue repair
 Failure to provide adequate nonprotein energy sources will lead to dissolution
of lean tissue stores
 Requirement for energy may be measured by indirect calorimetry or
estimated from urinary nitrogen excretion, which is proportional to resting
energy expenditure
Basal energy expenditure may also be estimated using the Harris Benedict
equation:

BEE (men) = 66.47 + 13.75 (W) + 5.0 (H) – 6.76 (A) kcal/d

BEE (women) = 655.1 + 9.56 (W) + 1.85 (H) – 4.68 (A) kcal/d

where W = weight in kilograms

H = height in centimeters
A = age in years

Total Caloric Requirements equal the B.E.E. multiplied by the sum of the stress
and activity factors. Stress plus activity factors range from 1.2 to over 2
Case of LQ, 30/M
Admitted for 3rd degree burns, anterior trunk, 18% BSA
Wt: 72 kg
Ht: 170 cm
What is the caloric requirement and protein requirement for this patient?
Case of LQ, 30/M
Admitted for 3rd degree burns, anterior trunk, 18% BSA
Wt: 72 kg
Ht: 170 cm
What is the caloric requirement and protein requirement for this patient?

BEE (men) = 66.47 + 13.75 (W) + 5.0 (H) – 6.76 (A) kcal/d
Case of LQ, 30/M
Admitted for 3rd degree burns, anterior trunk, 18% BSA
Wt: 72 kg
Ht: 170 cm
What is the total caloric requirement and protein requirement for this patient?

BEE (men) = 66.47 + 13.75 (72) + 5.0 (170) – 6.76 (30) kcal/d
BEE = 1703.67 kcal/d
Case of LQ, 30/M
Admitted for 3rd degree burns, anterior trunk, 18% BSA
Wt: 72 kg
Ht: 170 cm
What is the total caloric requirement and protein requirement for this patient?

BEE (men) = 66.47 + 13.75 (72) + 5.0 (170) – 6.76 (30) kcal/d
BEE = 1703.67 kcal/d
BEE x 2.0 (burns) = 3407.34 kcal/day
Protein requirement per day = 2.5g (burns) x 72 kg/d = 180g protein/day
 After trauma or sepsis, energy
substrate demands are increased
during the recovery phase and may
necessitate greater nonprotein
calories beyond calculated energy
expenditure
 This equation is suitable for estimating energy requirements in over 80% of
hospitalized patients

 Provision of 25-30kcal/kg per day will adequately meet energy requirements

in most postsurgical patients with low risk of overfeeding
 Vitamins and Minerals
 Vitamins are usually not given in the absence of preoperative deficiencies

 Patients maintained on elemental diets or parenteral hyperalimentation

require complete vitamin and mineral supplementation
 Major manifestations of deficiencies
 Vitamins
 Vit A night blindness, corneal drying
 Vit D rickets, osteomalacia, bone pain
 Vit E chronic cholestasis, hyporeflaxia
 Vit K hemorrhagic disorders
 Thiamin (B1) dry beriberi, wet beriberi
 Riboflavin sebaceous gland inflammation
 Niacin dermatosis, pellagra
 Pyridoxine (B6) peripheral neuropathy
 Biotin dry and scaling skin, glossitis
 Vit B12 pernicious anemia, neuropathy, myelopathy,
glossitis
 Folic acid similar to B12 def
 Pantothenic acid headache, insomnia, paresthesias
 Vit C scurvy, perifollicular hemorrhage
 Essential fatty acids
hair loss, dry skin, eczematoid dermatosis
 Major manifestations of deficiencies
 Minerals
 Calcium dementia, encephalopathy, tetany
 Phosphorus mental status changes, hemolysis,
paresthesias
 Potassium respiratory failure, paralytic ileus, tetany,
arrhythmias
 Magnesium hypocalcemia, hypokalemia, neuromuscular
spasms, gut malabsorption
 Iodine goiter
 Iron microcytic anemia, fatigue, dyspepsia
 Zinc dermatosis, photopobia, night blindness,
impaired wound healing, alopecia, diarrhea
 Fluoride no acute clinical signs
 Selenium cardiomyopathy, myalgia, white nail beds
 Chromium glucose intolerance
 Cobalt no acute signs known
 Molybdenum headache, night blindness, lethargy
 Manganese hair thinning, weight loss, dermatitis
 Overfeeding
 Overfeeding usually results from overestimation of caloric needs as occurs
when BW is used to calculate the BEE in such patient populations as the
critically ill with significant fluid overload and the obese
 Enteral Nutrition
 Generally preferred over parenteral nutrition based on reduced cost and
associated risks of the IV route
 Studies comparing postoperative enteral and parenteral nutrition in patients
undergoing GI surgery have been demonstrated reduced infection
complications and acute phase protein production when fed by the enteral
route
 Patients with adequate nutritional status have an albumin level of ≥4 g/dL
 Moderate malnutrition 2.9 to 3.5 g/dL
 Early enteral nutrition is recommended for surgical patients who are moderately
malnourished
 Enteral Formulas
 Low-Residue Isotonic Formulas
 Isotonic Formulas with Fiber
 Immune-Enhancing Formulas
 Calorie-Dense Formulas
 High-Protein Formulas
 Elemental Formulas
 Renal-Failure Formulas
 Pulmonary-Failure Formulas
 Hepatic- Failure Formulas
 Options for Enteral Feeding Access

 Nasogastric tube – short-term use, with aspiration risk,

nasopharyngeal trauma, frequent dislodgment
 Nasoduodenal/nasojejunal – short-term use, lower
aspiration risk in jejunum, radiographic assistance
necessary
 Percutaneous endoscopic gastrostomy (PEG) –
endoscopy skills, for gastric decompression or bolus
feed, with aspiration risk, lasts 1-2 years,
complications: placement and site leaks
 Surgical gastrostomy – done under GA and small
laparotomy/laparoscopy, can be placed with extended
duodenal/jejunal feeding ports
 Fluoroscopic gastrostomy – blind placement with
needle and T-prongs to anchor stomach, can thread
smaller catheter through gastrostomy into
duodenum/jejunum under fluoroscopy
 Options for Enteral Feeding Access
 PEG + Jejunal tube – two-stage procedure with PEG placement, followed by
fluoroscopic/endoscopic conversion with jejunal feeding tube through PEG, jejunal
tube often dislodges retrograde
 Direct percutaneous endoscopic jejunostomy (DPEJ) - direct endoscopic tube
placement with enteroscope/colonoscope, placement challenges in locating
suitable jejunal site, greater injury risks but less frequent tube malfunction than
PEG-J with placement of large caliber catheters
 Surgical jejunostomy – laparotomy/laparoscopy
 Absolute contraindication: distal intestinal obstruction
 Can be used for patient with complex abdominal or trauma surgery
 Fluoroscopic jejunostomy - difficult approach with injury risks, not commonly done
 Parenteral Nutrition
 Involves the continuous infusion of a hyperosmolar solution containing
carbohydrates, proteins, fats and other necessary nutrients through an
indwelling catheter inserted into the superior vena cava
 Requires adequate calorie to protein ratio and must be infused simultaneously to
prevent decreased nitrogen utilization
 Short-term use of parenteral nutrition in critically ill patients (duration < 7
days) when enteral nutrition may have been instituted is associated with
higher rates of infectious complications
 Following severe injury, parenteral nutrition is associated with higher rates
of infectious risks when compared with enteral feeding
 Rationale for Parenteral Nutrition
 Principal indications for parenteral nutrition are found in seriously ill patients
suffering from malnutrition, sepsis or surgical or accidental trauma, when
use of the GIT for feedings is not possible
 Can also be used to supplement enteral nutrition after 1 week of use if
enteral nutrition is unable to meet >60% of energy and protein
requirements
 In some instances, IV nutrition may be used to supplement inadequate oral
intake
 Situations in which parenteral nutrition
has been used
1. Newborn infants with catastrophic 4. Surgical patients with prolonged
gastrointestinal anomalies (TEF, paralytic ileus following major
gastroschisis, omphalocoele, massive operations, multiple injuries, blunt or
intestinal atresia)
open abdominal trauma, reflex ileus,
2. Infants who fail to thrive due to complicating various medical diseases
gastrointestinal insufficiency associated
5. Patients with normal bowel length but
with short bowel syndrome, malabsorption,
enzyme deficiency, meconium ileus or with malabsorption secondary to sprue,
idiopathic diarrhea hypoproteinemia, enzyme or pancreatic
insufficiency, regional enteritis or
3. Adults with short bowel syndrome
ulcerative colitis
secondary to massive small bowel
resection 6. Adult patients with functional GI
4. Entero-enteric, entero-colic, entero-vesical, disorders such as esophageal
or high output entero-cutaneous fistula dyskinesia following cerebrovascular
accident, idiopathic diarrhea,
psychogenic vomiting or anorexia
8. Adult patients with functional GI disorders such as esophageal dyskinesia
following cerebrovascular accident, idiopathic diarrhea, psychogenic vomiting
or anorexia nervosa
9. Patients with malignancy with or without cachexia in whom malnutrition
might jeopardize successful delivery of a therapeutic option
10. Failed attempts to provide adequate calories by enteral tube feeding or high
residuals
11. Critically ill patients who are hyper metabolic for more than 5 days or when
enteral nutrition is not feasible
 Complications of Parenteral Nutriton
Technical Complications:
 Sepsis secondary to contamination of the central venous catheter
 Pneumothorax
 Hemothorax
 Hydrothorax
 Subclavian artery injury
 Thoracic duct injury
 Cardiac arrhythmia
 Air embolism
 Catheter embolism
 Cardiac perforation with tamponade
Metabolic Complications:
 Hyperglycemia may develop with normal rates on infusion in patients with impaired
glucose tolerance or in any patient if the hypertonic solutions are administered too
rapidly
 Excess feeding also has been related to the development of hepatic steatosis or marked
glycogen deposition in selected patients
 Cholestasis and formation of gallstones are common in px receiving long term
parenteral nutrition
 Mild but transient abnormalities of serum transaminase, alkaline phosphatase and
bilirubin may occur in many parenterally nourished patients
Intestinal Atrophy
 Lack of intestinal stimulation is associated with:
 Intestinal mucosal atrophy
 Diminished villous height
 Bacterial overgrowth
 Reduced lymphoid tissue size
 Reduced IgA production
 Impaired gut immunity
Thank You!!!
 Quiz
1. Which of the following patients may benefit from enteral nutrition? (Select
all that apply.)

A. A patient who has a brain injury

B. A patient with oral cancer
C. A patient with paralytic ileus
D. A patient with burns of the lower extremities
 Quiz
1. Which of the following patients may benefit from enteral nutrition? (Select
all that apply.)

A. A patient who has a brain injury

B. A patient with oral cancer
C. A patient with paralytic ileus
D. A patient with burns of the lower extremities
 Quiz

2. Which of the following accurately describes the greatest risk related to

having a feeding tube?

A. Electrolyte imbalance
B. Fluid volume overload
C. Infection
D. Aspiration
 Quiz

2. Which of the following accurately describes the greatest risk related to

having a feeding tube?

A. Electrolyte imbalance
B. Fluid volume overload
C. Infection
D. Aspiration
 Quiz
3. Which of the following is accurate about SIRS?

A. The pathophysiologic properties of SIRS widely vary, depending on the

etiology
B. SIRS only develops when a localized aggressive injury process gains access
to the whole body through the blood stream and lymphatics
C. Women with SIRS tend to have more inflammation from the same degree of
proinflammatory stimuli and have a worse mortality risk than men
D. All patients with SIRS require hospitalization, as they have diseases that
ultimately progress to serious illnesses
 Quiz
3. Which of the following is accurate about SIRS?

A. The pathophysiologic properties of SIRS widely vary, depending on the

etiology
B. SIRS only develops when a localized aggressive injury process gains access
to the whole body through the blood stream and lymphatics
C. Women with SIRS tend to have more inflammation from the same degree of
proinflammatory stimuli and have a worse mortality risk than men
D. All patients with SIRS require hospitalization, as they have diseases that
ultimately progress to serious illnesses
 Quiz
4. Which of the following is accurate about the workup of SIRS?

A. Bacteriologic cultures should be stressed in the diagnostic workup of patients

with suspected SIRS
B. An increased percentage of bands on white blood cell count is associated with
a decreased incidence of infectious causes of SIRS
C. Elevated blood lactate levels typically decrease in response to fluid
resuscitation in patients with SIRS
D. Serum leptin is the criterion standard for differentiation of sepsis from
noninfectious SIRS, with a cutoff of 30 µg/L
 Quiz
4. Which of the following is accurate about the workup of SIRS?

A. Bacteriologic cultures should be stressed in the diagnostic workup of patients

with suspected SIRS
B. An increased percentage of bands on white blood cell count is associated with
a decreased incidence of infectious causes of SIRS
C. Elevated blood lactate levels typically decrease in response to fluid
resuscitation in patients with SIRS
D. Serum leptin is the criterion standard for differentiation of sepsis from
noninfectious SIRS, with a cutoff of 30 µg/L
 Quiz
5.Which of the following is accurate about the treatment of SIRS?

A. TNF-alpha and IL-1 receptor antagonists are first-line treatments for patients
with SIRS
B. Typically, platelet-activating factor receptor antagonists and anticoagulants
(antithrombin III) are routinely indicated in patients with SIRS
C. Enteral feedings supplemented with arginine and omega-3 fatty acids are
typically beneficial in patients with SIRS
D. Initially, a short course of high doses of steroids is recommended in patients
with SIRS
 Quiz
5.Which of the following is accurate about the treatment of SIRS?

A. TNF-alpha and IL-1 receptor antagonists are first-line treatments for patients
with SIRS
B. Typically, platelet-activating factor receptor antagonists and anticoagulants
(antithrombin III) are routinely indicated in patients with SIRS
C. Enteral feedings supplemented with arginine and omega-3 fatty acids are
typically beneficial in patients with SIRS
D. Initially, a short course of high doses of steroids is recommended in patients
with SIRS
 Quiz
6. The vagus nerve mediates which of the following in the setting of systemic
inflammation?

A. Enhanced gut motility

B. Decreased protein production by the liver
C. Decreased tumor necrosis factor (TNF) production
D. Increased heart rate to increase cardiac output
 Quiz
6. The vagus nerve mediates which of the following in the setting of systemic
inflammation?

A. Enhanced gut motility

B. Decreased protein production by the liver
C. Decreased tumor necrosis factor (TNF) production
D. Increased heart rate to increase cardiac output
 Quiz
7. The primary source of calories during acute starvation (5 days fasting) is?

A. Fat
B. Muscle (protein)
C. Glycogen
D. Ketone bodies
 Quiz
7. The primary source of calories during acute starvation (5 days fasting) is?

A. Fat
B. Muscle (protein)
C. Glycogen
D. Ketone bodies
 Quiz
8. Sepsis increases metabolic needs by approximately what percentage?

A. 25%
B. 50%
C. 75%
D. 100%
 Quiz
8. Sepsis increases metabolic needs by approximately what percentage?

A. 25%
B. 50%
C. 75%
D. 100%
 Quiz
9. Which of the following is a potential physiologic effect of anabolism (positive
nitrogen balance)?

A. Glycosuria
B. Metabolic acidosis
C. Hypercalcemia
D. Hypermagnesemia
 Quiz
9. Which of the following is a potential physiologic effect of anabolism (positive
nitrogen balance)?

A. Glycosuria
B. Metabolic acidosis
C. Hypercalcemia
D. Hypermagnesemia
 Quiz
10. Overfeeding in a critically ill patient can result in?

A. Pancreatitis
B. Increased risk of infection
C. Atelectasis
D. Increased risk of DVT
 Quiz
10. Overfeeding in a critically ill patient can result in?

A. Pancreatitis
B. Increased risk of infection
C. Atelectasis
D. Increased risk of DVT
Bonus for 1 point:
3 hormones that promote gluconeogenesis in stressed or injured states?
Bonus for 1 point:
3 hormones that promote gluconeogenesis in stressed or injured states?
Epinephrine, cortisol, glucagon